CN105326838A - 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one for the treatment of lung function - Google Patents

Abstract

A compound which is a hydroxyquinolinone derivative of formula (I), in the form of a racemate, a steroisomer or a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, for use in normalising the lung function of a human patient.

Description

Be used for the treatment of 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one of pulmonary function

The application is the divisional application that the application number submitted on February 18th, 2010 is PCT/EP2010/001026, denomination of invention is the international application of " 5-(2-{ [6-(2; the fluoro-2-phenyl ethoxy of 2-bis-) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one being used for the treatment of pulmonary function ", described international application enters National Phase in China on August 18th, 2011, and its application number is 201080008363.X.

[technical field]

The present invention relates to the method for the normal pulmonary function making patient.

[background technology]

5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one is a kind of effective, long-acting and optionally beta 2 adrenoreceptor agonist.It is described in WO2006/122788.It is with the hydroxyquinoline ketone derivatives of following formula (I):

The salt form of this compound is described in WO2008/095720.

Long-acting beta 2 adrenoreceptor agonist available at present comprises salmaterol (salmeterol) (2-(methylol)-4-{1-hydroxyl-2-[6-(4-phenylbutoxy) hexyl amido] ethyl } phenol) and formoterol (formoterol) (N-[2-hydroxyl-5-[1-hydroxyl-2-[1-(4-methoxyphenyl) third-2-base amido] ethyl] phenyl] Methanamide).

There is the multiple method measuring the pulmonary function of patient.These methods comprise peak flow, body volume cardiotokography and the vital capacity measurement method of measuring patient.Vital capacity measurement method comprises the amount and/or speed of measuring the air that patient can suck or breathe out.Basis vital capacity measurement method test generally comprises patient and tries one's best deeply to have a suck of gas and then exhale in the blow gun being equipped with induction apparatus, and this induction apparatus can measure volume and/or the speed of air-out.The availability value of the pulmonary function measured by which is the FEV1 value of patient.FEV1 (1 second forced expiratory volume, ForcedExpiratoryVolumein1second) is the maximum air capacity that patient can breathe out in 1 second.The reference FEV1 value desired by normal healthy people with specific body weight and height is value disclosed in following article: the people such as Quanjer theEuropeanRespiratoryJournal: the 6 volume, supplementary issue 16,5-40 page, in March, 1993 and name are called " LungVolumesandForcedVentilatoryFlows-ReportWorkingParty-StandardizationofLungFunctionTest-EuropeanCommunityforSt eelandCoal-OfficialStatementoftheEuropeanRespiratorySoci ety ".

Pulmonary function reduces and may be mediated by multiple different pathogeny.Its usual and such as asthma or chronic obstructive pulmonary disease (ChronicObstructivePulmonaryDisease; Etc. COPD) respiratory passage diseases is correlated with, but it also may be produced by neural or macular disease (such as muscular dystrophy), or even produces in the situations such as such as stomach-esophageal reflux (gastro-oesophagealreflux).

Suffer from patient that pulmonary function reduces usually to experience and breathe uncomfortable and difficulty (dyspnea), this has extreme influence, if especially like this when it is caused by chronic disease to patient tolerance's motion or the ability of carrying out its normal daily routines.In the long term, the ability reduction of tolerated exercise can be causeed fat and cardiovascular disorder.It is also very important for maintaining enough pulmonary functions night.Night, low FEV1 value can cause the event of nocturnal dyspnea and sleep disorder.It may be life-threatening situation that acute pulmonary function is reduced in some patients, and even causes death because suffocating.

Therefore, need treatment patient to make its normal pulmonary function, especially increase its FEV1 value, make it close to the value desired by normal health patient.Make the normal pulmonary functionization of patient can improve the quality of life at its daytime and night in like fashion, alleviate breathing uncomfortable and difficult, and increase the toleration to motion.Normal pulmonary function is made rapidly when also needing in serious acute respiratory difficulty and suffocate.

Oneself finds that 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one has unexpected high effect in the pulmonary function (especially FEV1) increasing the patient that experience pulmonary function reduces.5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one can make the pulmonary function of patient and FEV1 normalization to the value be essentially desired by normal healthy people.5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one improves effect of FEV1, and than using other, oneself knows long-acting beta agonist (longactingbetaagonist; LABA) (such as salmaterol) viewed effect is much bigger.

[summary of the invention]

Therefore; in a first embodiment; the invention provides a kind of compound; this compound is the 5-(2-{ [6-(2 of racemic modification, stereoisomer or stereoisomer mixture form; 2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one or its pharmaceutically acceptable salt or solvate, described compound is used for by sucking the normal pulmonary function making human patients.

According to especially preferred embodiment of the present invention, compound of the present invention is particularly useful for treating the patient with intractable respiratory symptom; Be applicable to the maintenance therapy to the patient by bronchodilator (such as long-acting beta-adrenaline agonist) therapeutic response deficiency; Or be applicable to treat the patient that there is severe lung function and reduce.

Another preferred embodiment of the present invention is 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one also can be acute as first aid medicine (rescuemedication), such as in breathing in emergency circumstances.

[detailed Description Of The Invention]

The mean F EV1 value (liter) of 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one (being called in figure " compound 1 ") that Fig. 1 illustrates single dose (25 microgram) (hour) and change in time.It also illustrates the mean F EV1 value after administered twice (time point is 0 hour and 12 hours) 50 microgram salmaterol and single administration placebo.

Term " treatment effective dose (therapeuticallyeffectiveamount) " refers to the amount being enough to realize therapeutical effect when using to the patient of needs treatment.

As used herein, " over much dosage (supramaximaldose) " produces the dosage of the dosage of maximum effect for being equal to or greater than specific compound.

Term " suitable dosage (appropriatedose) " refers to thinks treatment particular patient necessary dosage.It can be the dosage containing " treatment effective dose " or " over much dosage ", this initial level according to disease, patient, pulmonary function, treatment persistent period or frequency of administration and determine.

Effect of 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one so high so that its can be advantageously used in various patient that pulmonary function reduces and have nothing to do with the cause of disease.This comprises the patient with intractable (be namely difficult to treat) the respiratory symptom dyspnea of the such as persistence (, cough or breathe), or as hereafter the patient with especially serious pulmonary function reduction that defines.

Compound of the present invention is particularly useful for patient's (also referred to as maintaining treatment) that continued treatment has chronic pulmonary functional lesion, because it has long acting duration and once uses by only sucking every day.In addition, because effect of compound of the present invention is much higher compared with can be used for increasing the medicine (such as beta-adrenaline agonist, cholilytic drug (anticholinergicagent) or other bronchodilator) of pulmonary function at present, therefore it can be used for treating the hyporeactive patient to described medicine.It is more much bigger than salmaterol that following instance shows the effect that compound of the present invention produces FEV1.

It is believed that; when patient continues to have symptom or when the FEV1 value of patient is lower than " normalization (normalised) " value hereinafter described; although treat with the bronchodilator of suitable dosage or the other medicines for improving pulmonary function, patient is also to the underaction by described Drug therapy.

Usually, as used herein, to the hyporeactive patient of bronchodilator therapy be after every daily 50 microgram salmaterol treatment twice FEV1 value lower than the patient of normalization value shown below.When not increasing by 200 milliliters or more in the FEV1 value of A Single Intake by Inhalation 400 microgram albuterol (salbutamol) patient afterwards, also think the underaction of described patient to bronchodilator (being more specifically beta-adrenaline agonist).

In addition, due to its high effect and quick acting (obviously faster than one of salmaterol), therefore 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one is may because having the potential help advantage as first aid medicine in the breathing emergency (such as severe asthma attacks, exercise induced bronchoconstriction or anaphylactic reaction) of dying of asphyxiation.In these cases, compared with the beta-adrenaline agonist (as albuterol) being commonly used for first aid medicine with other, use compound of the present invention especially favourable.The time that the higher and fast effect lasts of compound of the present invention is much longer, this contributes to reducing acute pulmonary function and reduces and the recurrence of other emergency.

Term " pharmaceutically acceptable salt " refers to by being administered to patient (such as mammal) acceptable alkali or the standby salt of processed with acid.Described salt can derived from pharmaceutically acceptable inorganic base or organic base and pharmaceutically acceptable mineral acid or organic acid.

Salt derived from pharmaceutically acceptable acid comprises: acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid (napadisilate), nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid, former times U.S. acid (xinafoic) (1-hydroxy-2-naphthoic acid) salt etc.Especially be preferably derived from fumaric acid, hydrobromic acid, hydrochloric acid, acetic acid, sulphuric acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, former times U.S. acid and tartaric salt.Most preferably be the salt derived from methanesulfonic acid and naphthalene-1,5-disulfonic acid.

The normally single napadisilate (mononapadisylate) of salt derived from naphthalene-1,5-disulfonic acid or half napadisilate (heminapadisylate) and its pharmaceutically acceptable solvate.

Usually, naphthalene-1, the 5-disulfonate of compound of the present invention has formula (II):

Wherein n has the value of 1 or 2.

Salt derived from methanesulfonic acid is also referred to as mesylate.

Salt derived from pharmaceutically acceptable inorganic base comprises: aluminum, ammonium, calcium, copper, ferrum, ferrous iron, lithium, magnesium, manganese, sub-manganese, potassium, sodium, zinc salt etc.Especially ammonium, calcium, magnesium, potassium and sodium salt is preferably.

Salt derived from pharmaceutically acceptable organic base comprises primary amine, the salt of secondary amine and tertiary amine, described amine comprises the amine be substituted, cyclammonium, naturally occurring amine etc., such as spermine acid, betanin, caffeine, gallbladder alkali, N, N '-benzhydryl ethylenediamine, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glycosamine, histidine, hetramine (hydrabamine), 2-aminopropane., rely amino acid, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine (procaine), purine, Theobromine (theobromine), triethylamine, trimethylamine, tripropyl amine (TPA), trometamol (tromethamine) etc.

Term " solvate " refers to the complex or aggregation that are formed by one or more solute molecule (i.e. compound of the present invention or its pharmaceutically acceptable salt) and one or more solvent molecule.Described solvate normally has the crystalline solid of the solute of substantial constant and the mol ratio of solvent.Representative solvents comprises (such as) water, methanol, ethanol, isopropyl alcohol, acetic acid etc.When solvent is water, the solvate formed is hydrate.

Compound of the present invention contains chiral centre.Therefore, its can racemic mixture, enantiomer or one or more stereoisomers of enrichment mixture form use.As address the present invention for required protection scope contain the racemic form of compound of the present invention and the mixture of indivedual enantiomer and enrichment stereoisomer.

Most preferred enantiomer is 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one.

Should be appreciated that, term " or its pharmaceutically acceptable salt or solvate " is intended to all changes combination comprising salt and solvate, the solvate of the pharmaceutically acceptable salt of such as the compounds of this invention.

As used herein, mention " making the normal pulmonary function of human patients " refer to especially increase FEV1 lower than as hereafter the FEV1 of the patient of expectation normal value that defines, until the normal FEV1 of the expectation being essentially described patient.

The normal FEV1 of expectation of patient can determine based on the age of patient, height and sex.Therefore, the FEV1 value of older patients is usually low than the young patient with identical height and sex.The FEV1 value of higher patient is usually high than the shorter patient with same age and sex.The FEV1 value of female patient is usually low than the male patient with same age and height.

Determine that the normal FEV1 of the expectation of patient is the complete routine work of chest physician.Usually, by algorithm or by consulting the standard scale estimating normal FEV1 value, use the height of patient, age and sex to determine the normal FEV1 of patient.Described form is widely available, and with people such as above-mentioned Quanjer, based on the research of 1993.According to this research, the expectation FEV1 of normal human subject can be calculated by means of following formula:

-male: 4.3H-0.029A-2.49

-women: 3.95H-0.025A-2.6

Wherein H=height (rice) and the A=age (year).

Usually, as used herein, the normal FEV1 of the expectation of patient is determined with reference to these formulas.

Usually measured the FEV1 of patient with experiment method by vital capacity measurement method.Measuring FEV1 by vital capacity measurement method is the standard technique known in division of chest disease's Medical Technology.When assessing the pulmonary function after using medicament, generally measure the FEV1 of patient upon administration with regular interval.When determining effect of medicament, the metric be especially suitable for that can carry out is baseline FEV1, peak F EV1 and valley FEV1.

As used herein, baseline FEV1 be use medicament before the FEV1 of patient.

As used herein, peak F EV1 is the maximum FEV1 of initial 3 hours, 4 hours, 5 hours periods patient after using medicament.For example, for measure use medicament after maximum FEV1 in initial 3 hours, the FEV1 of Timing measurement patient in initial 3 hours, measures once for such as every 30 minutes.

As used herein, valley FEV1 is at the FEV1 using patient measured between latter 22 hours and 24 hours of medicament (such as compound of the present invention).Within 23 hours, be measure to be suitable for the appropriate time point of the valley FEV1 of the compound of once-a-day administration, but same acceptable substituting time point it is after administration 22 hours or 24 hours in this case.The meansigma methods of the FEV1 value after administration measured by 23 hours and 24 hours is also the common reference value of valley FEV1.

The patient of normal pulmonary function is made usually to have the baseline FEV1 (namely before administered compound) of 90% of the normal FEV1 of the expectation being less than described patient by compound of the present invention.In a particular embodiment, baseline FEV1 is less than 85% or 80% or 75% of the normal FEV1 of expectation of described patient.In other embodiments, baseline FEV1 is less than 70% or 65% or 60% of the normal FEV1 of expectation of described patient.

When clinical trial hereinafter described, the baseline FEV1 of patient is 61% to 85% of predicted value, it is according to people such as Bateman, Eur.Resp.J., 31 (1): 143.178,2008 prevented and treated by global asthma proposes (GlobalInitiativeforAsthma, GINA) disclosed criterion, corresponding to suffering from slightly to the patient of moderate persistent asthma.

In view of the high effect using slight/moderate patient viewed compound in this experiment, obvious special benefit is suffer from the patient that especially serious pulmonary function reduces in one group of patient of the present invention.According to the GINA criterion (its pulmonary function that can be applicable to any cause of disease reduces) about FEV1 value, it is equal to or less than the situation of the patient of 60% of the normal FEV1 of expectation of described patient for baseline FEV1.

From clinical point; if (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period), the mean F EV1 of a group human patients was increased to the low value being not less than a certain percentage ratio of the normal FEV1 of average expectation organized than described patient, then the pulmonary function of described patient group obtains " normalization " usually.When the mean F EV1 value that described patient organizes is relative to the average baselining FEV1 of patient or when increasing a certain amount (in milliliter or with percentages) relative to the mean F EV1 value obtained when using placebo to described patient, also achieve the normalization of pulmonary function and FEV1.Therefore, should be explained by this clinical point for the specific FEV1 value described in independent patient in following paragraph.

Therefore; the average peak FEV1 of (if depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) human patients be increased to lower than the normal FEV1 of the expectation of described patient be not less than 30% value; preferably be increased to the value that be not less than 25% or 20% or 15% lower than the normal FEV1 of the expectation of described patient; more preferably be increased to the value that be not less than 10% or 5% lower than the normal FEV1 of average expectation of described patient, then the pulmonary function of described human patients and FEV1 obtain " normalization " usually.

Daily once when, compound of the present invention is used usually in the morning.Therefore, the peak F EV1 (namely little in 5 hours 2) within a few hours of normalization, realizes when in one day, needs of patients has the maximum pulmonary function being suitable for carrying out its normal daily routines.

In addition; the valley FEV1 of (if the order of severity and baseline FEV1 value depending on disease) human patients be increased to lower than the normal FEV1 of the expectation of described patient be not less than 40% value; preferably be increased to the value that be not less than 35% or 30% or 25% lower than the normal FEV1 of the expectation of described patient; more preferably be increased to the value that be not less than 15% or 10% lower than the normal FEV1 of the expectation of described patient, then the pulmonary function of described patient and FEV1 obtain " normalization " usually.

Daily once when, the valley FEV1 of these normalizations by be enough to make patient have tranquil sleep and without nocturnal dyspnea event and without the need to using other bronchodilator any.

As described above, compound of the present invention makes normal pulmonary function by making the peak value of patient and valley FEV1 be increased to more than the baseline FEV1 of the patient used before compound of the present invention.The peak value obtained when compound of the present invention is also by making the peak value of patient and valley FEV1 be increased to and be administered to patient comfort's agent and more than valley FEV1 and make normal pulmonary function.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the peak F EV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) increase above 400 milliliters relative to the baseline FEV1 of patient.Preferably, using compound of the present invention makes peak F EV1 increase above 450 milliliters, 500 milliliters or 550 milliliters relative to baseline FEV1.More preferably, it increases above 600 milliliters, 650 milliliters or 700 milliliters.Most preferably, compound of the present invention makes peak F EV1 increase above 750 milliliters or 800 milliliters relative to baseline FEV1, with especially like this during single over much dosage form administration.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the peak F EV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) increase above 9% relative to the baseline FEV1 of described patient.Preferably, using compound of the present invention makes peak F EV1 increase above 12%, 15% or 18% relative to baseline FEV1.More preferably, it increases above 21% or 24%.Most preferably, compound of the present invention makes peak F EV1 increase above 27% relative to baseline FEV1, with especially like this during single over much dosage form administration.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the valley FEV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) increase above 150 milliliters relative to the baseline FEV1 of described patient.Preferably, using compound of the present invention makes valley FEV1 increase above 200 milliliters, 250 milliliters or 300 milliliters relative to baseline FEV1.More preferably, 350 milliliters, 400 milliliters or 450 milliliters are increased above.Most preferably, compound of the present invention makes valley FEV1 increase above 500 milliliters, 550 milliliters or 600 milliliters relative to baseline FEV1, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the valley FEV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) increase above 5% relative to the baseline FEV1 of described patient.Preferably, using compound of the present invention makes valley FEV1 increase above 7%, 9% or 11% relative to baseline FEV1.More preferably, 13%, 15% or 17% is increased above.Most preferably, compound of the present invention makes valley FEV1 increase above 19%, 21% or 23% relative to baseline FEV1, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the peak F EV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) relative to measured peak F EV1 when being administered to described patient comfort's agent and increases above 250 milliliters.Preferably, using compound of the present invention makes peak F EV1 increase above 300 milliliters, 350 milliliters or 400 milliliters relative to the peak F EV1 of placebo.More preferably, 450 milliliters or 500 milliliters are increased above.Most preferably, compound of the present invention makes peak F EV1 increase above 550 milliliters or 600 milliliters relative to the peak F EV1 of placebo, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the peak F EV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) relative to measured peak F EV1 when being administered to described patient comfort's agent and increases above 7%.Preferably, using compound of the present invention makes peak F EV1 increase above 9%, 11% or 13% relative to the peak F EV1 of placebo.More preferably, 15% or 17% is increased above.Most preferably, compound of the present invention makes peak F EV1 increase above 19% relative to the peak F EV1 of placebo, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the valley FEV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) relative to measured valley FEV1 when being administered to described patient comfort's agent and increases above 100 milliliters.Preferably, using compound of the present invention makes valley FEV1 increase above 150 milliliters, 200 milliliters, 250 milliliters, 300 milliliters or 350 milliliters relative to the valley FEV1 of placebo.More preferably, 400 milliliters, 450 milliliters, 500 milliliters or 550 milliliters are increased above.Most preferably, compound of the present invention makes valley FEV1 increase above 580 milliliters, 620 milliliters or 660 milliliters relative to the valley FEV1 of placebo, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention (using with single dose form or with the suitable dosage sucking form once or twice lasting every day) makes the valley FEV1 of patient (depending on the order of severity of disease, baseline FEV1 value and treatment persistent period) relative to measured valley FEV1 when being administered to described patient comfort's agent and increases above 3%.Preferably, using compound of the present invention makes valley FEV1 increase above 5%, 7% or 9% relative to the valley FEV1 of placebo.More preferably, 11%, 13% or 15% is increased above.Most preferably, compound of the present invention makes valley FEV1 increase above 17%, 19% or 21% relative to the valley FEV1 of placebo, with especially like this during the administration of single over much dosage.

Usually, compound of the present invention is used by sucking.Compound of the present invention is used preferably by being sucked by inhaler or aerosol apparatus.

Usually, compound of the present invention is in the medical composition comprising any applicable excipient or pharmaceutically acceptable supporting agent, and in the dry powder being suitable for sucking or solution form.

Usually, the amount that compound of the present invention is used when each suction is equivalent to 25 micrograms or less metering nominal standard dose used with Diskus.Term " metering nominal standard dose " refers to the amount of medicine contained in the measuring room of delivery apparatus, and is typically expressed as each amount sucked.After actuating, medicine leaves described device and with so-called " injection dosage ", patient can be used, and due to the mechanical property of device, therefore described injection dosage is less than metering nominal standard dose usually.

Usually, compound of the present invention be with single dose form of therapy or with once a day or the continued treatment form of multidose use, be preferably every day 1 time to 4 times dosage, be more preferably 1 time to 2 times dosage every day, be even more preferably 1 dosage every day.

Usually, the hydroxyquinoline ketone derivatives of formula (I) is selected from (R, S) 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one and 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1 (R)-ethoxy)-oxine-2 (1H)-one.

The hydroxyquinoline ketone derivatives of formula (I) preferably exists with R-enantiomeric forms.

Or the hydroxyquinoline ketone derivatives of formula (I) exists with S-enantiomeric forms.

Usually, compound of the present invention is the pharmaceutically acceptable salt of the hydroxyquinoline ketone derivatives of formula as herein defined (I).Preferably, compound of the present invention is the mesylate of the hydroxyquinoline ketone derivatives of formula as herein defined (I), single napadisilate or half napadisilate.

Preferably, the hydroxyquinoline ketone derivatives of formula (I) is selected from one of following compounds: 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1 (R)-hydroxy-ethyl)-oxine-2 (1H)-one half napadisilate or its pharmaceutically acceptable solvate, and 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1 (R)-hydroxy-ethyl)-oxine-2 (1H)-one mesylate or its pharmaceutically acceptable solvate.

Usually, described compound is used jointly with the another kind of therapeutic agent for the treatment of effective dose.

Described another kind of therapeutic agent is corticosteroid (corticosteroid), cholilytic drug and/or PDE4 inhibitor normally.

The example of the PDE4 inhibitor be applicable to is maleic acid hydrogen benafentrine (benafentrinedimaleate), etazolate (etazolate), denbufylline (denbufylline), rolipram (rolipram), Cipamfylline (cipamfylline), zardaverine (zardaverine), arofylline (arofylline), filaminast (filaminast), Tai Lusite (tipelukast), Tuo Feisite (tofimilast), Piclamilast (piclamilast), tolafentrine (tolafentrine), beautiful Suo Pulan (mesopram), drotaverine hydrochloride (drotaverinehydrochloride), Li Ruisite (lirimilast), roflumilast (roflumilast), cilomilast (cilomilast), OGLEMILAST (oglemilast), A Pusite (apremilast), Tetomilast (tetomilast), filaminast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenethyl] pyridine (CDP-840), N-(the chloro-4-pyridine radicals of 3,5-bis-)-2-[1-(4-benzyl)-5-hydroxyl-1H-indol-3-yl]-2-side oxygen yl acetamide (GSK-842470), 9-(2-benzyl)-N6-methyl-2-(trifluoromethyl) adenine (NCS-613), N-(the chloro-4-pyridine radicals of 3,5-bis-)-8-methoxy quinoline-5-Methanamide (D-4418), 3-[3-(cyclopentyloxy)-4-mehtoxybenzyl]-6-(ethyl amido)-8-isopropyl-3H-purine hydrochlorate (V-11294A), 6-[3-(N, N-dimethyl amine formoxyl) phenyl sulfonyl]-4-(3-methoxyphenyl amido)-8-methylquinoline-3-carboxamide hydrochloride (GSK-256066), 4-[two (methylol) naphthalene-1-base of 6,7-diethoxy-2,3-]-1-(2-methoxy ethyl) pyridine-2 (1H)-one (T-440), (-)-trans-2-[3 '-[3-(N-cyclopropylamine formoxyl)-4-side Oxy-1,4-dihydro-1,8-naphthyridines-1-base]-3-fluorine biphenyl-4-base] cyclopropane-carboxylic acid (MK-0873), CDC-801, UK-500001, BLX-914, 2-methoxycarbonyl group-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexamethylene 1-ketone, along [4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) hexamethylene-1-alcohol, CDC-801, 5 (S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3 (S)-(3-methylbenzyl) piperidines-2-ketone (IPL-455903), ONO-6126 (EurRespirJ2003,22 (supplementary issues 45): summary 2557) and No. WO03/097613rd, PCT patent application case, No. WO2004/058729, No. WO2005/049581, salt required for protection in No. WO2005/123693 and No. WO2005/123692.

The corticosteroid be applicable to and the example of glucocorticoid (glucocorticoid) are prednisolone (prednisolone), methylprednisolone (methylprednisolone), dexamethasone (dexamethasone), dexamethasone sodium phosphate (dexamethasonecipecilate), naflocort (naflocort), deflazacort (deflazacort), acetic acid halopredone (halopredoneacetate), budesonide (budesonide), beclomethasone (beclomethasonedipropionate), hydrogen corticosterone (hydrocortisone), triamcinolone acetonide (triamcinoloneacetonide), fluocinolone acetonide (fluocinoloneacetonide), fluocinonide (fluocinonide), pivalic acid clocortolone (clocortolonepivalate), methylprednisolone aceponate (methylprednisoloneaceponate), dexamethasone palmitate (dexamethasonepalmitoate), tipredane (tipredane), vinegar third hydrogen corticosterone (hydrocortisoneaceponate), prednicarbate (prednicarbate), alclometasone diproionate (alclometasonedipropionate), halometasone (halometasone), methylprednisolone suleptanate (methylprednisolonesuleptanate), mometasone furoate (mometasonefuroate), rimexolone (rimexolone), the sour prednisolone of method (prednisolonefarnesylate), ciclesonide (ciclesonide), butixocort propionate (butixocortpropionate), RPR-106541, propanoic acid deprodone (deprodonepropionate), fluticasone propionate (fluticasonepropionate), fluticasone furoate (fluticasonefuroate), halobetasol propionate (halobetasolpropionate), loteprednol (loteprednoletabonate), butanoic acid betamethasone dipropionate (betamethasonebutyratepropionate), flunisolide (flunisolide), prednisone (prednisone), dexamethasone sodium phosphate (dexamethasonesodiumphosphate), triamcinolone (triamcinolone), 17-betamethasone valerate (betamethasone17-valerate), betamethasone (betamethasone), betamethasone dipropionate (betamethasonedipropionate), chloro-11 beta-hydroxyl-17 alphas of 21--[2-(methylsulfany) acetoxyl group]-4-pregnene-3,20-diketone, disappear isobutyryl ciclesonide (Desisobutyrylciclesonide), acetic acid hydrogen corticosterone (hydrocortisoneacetate), hydrogen corticosterone sodium succinate (hydrocortisonesodiumsuccinate), NS-126, prednisolone sodium phosphate (prednisolonesodiumphosphate) and propanoic acid butanoic acid hydrogen corticosterone (hydrocortisoneprobutate), sulfonic benzoic acid sodium (Prednisolonesodiummetasulfobenzoate) and clobetasol propionate (clobetasolpropionate) between prednisolone.

The example of the M3 antagonist (cholilytic drug) be applicable to is tiotropium (tiotropium) salt, oxygen holder ammonium (oxitropium) salt, fluorine holder ammonium (flutropium) salt, ipratropium (ipratropium) salt, GLYCOPYRRONIUM (glycopyrronium) salt, Trospium cation (trospium) salt, zamifenacin (zamifenacin), Revatropate (revatropate), espatropate (espatropate), NPC-14695, BEA-2108, 3-[2-hydroxyl-2, two (2-thienyl) acetoxyl group of 2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt (especially Ah 's ammonium (aclidinium) salt, be more preferably aclidinium bromide), 1-(2-phenethyl)-3-(9H-ton-9-base carbonyl oxygen base)-1-nitrogen dicyclo [2.2.2] octane salt, 2-side Oxy-1, 2, 3,-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester salt (DAU-5884) in 4-tetrahydro quinazoline-3-formic acid, 3-(4-benzyl piperazine-1-base)-1-cyclobutyl-1-hydroxyl-1-phenyl third-2-ketone (NPC-14695), N-[1-(6-amido pyridine-2-ylmethyl) piperidin-4-yl]-2 (R)-[3, fluoro-1 (the R)-cyclopenta of 3-bis-]-2-hydroxyl-2-phenyl-acetamides (J-104135), 2 (R)-cyclopenta-2-hydroxy-ns-[1-[4 (S)-methylhexyl] piperidin-4-yl]-2-phenyl-acetamides (J-106366), 2 (R)-cyclopenta-2-hydroxy-ns-[1-(4-methyl-3-pentenyl)-4-piperidyl]-2-phenyl-acetamides (J-104129), 1-[4-(2-amido ethyl) piperidin-1-yl]-2 (R)-[3, 3-difluoro ring penta-1 (R)-Ji]-2-hydroxyl-2-phenyl second-1-ketone (Banyu-280634), N-[N-[2-[N-[1-(cyclohexyl methyl) piperidines-3 (R)-ylmethyl] amine formyl] ethyl] amine formyl methyl]-3, 3, 3-triphenyl propionic acid amide. (BanyuCPTP), 2 (R)-cyclopenta-2-hydroxyl-2-phenylacetic acid 4-(own-3-base of 3-azabicyclo [3.1.0])-2-butyne ester (Ranbaxy364057), iodate 3 (R)-[4, 4-two (4-fluorophenyl)-2-sides oxygen base imidazolidine-1-base]-1-methyl isophthalic acid-[2-side oxygen base-2-(3-thienyl) ethyl] Pyrrolizidine, trifluoroacetic acid N-[1-(3-hydroxyphenylmethyl)-1-methyl piperidine-3 (S)-Ji]-N-[N-[4-(isopropoxy carbonyl) phenyl] amine formyl]-L-tyramine amide, UCB-101333, the OrM3 of Merck & Co., Inc. (Merck), in 7--(2-hydroxyl-2, 2-diphenyl acetoxyl group)-9, 9-dimethyl-3-oxa--9-nitrogen three ring [3.3.1.0 (2, 4)] nonane salt, iodate 3 (R)-[4, 4-two (4-fluorophenyl)-2-sides oxygen base imidazolidine-1-base]-1-methyl isophthalic acid-(2-phenethyl) Pyrrolizidine, the trans-4-of bromination from Novartis [2-[hydroxyl-2, 2-(two thiophene-2-bases) acetoxyl group]-1-methyl isophthalic acid-(2-Phenoxyethyl) piperidines (412682), 7-(2, 2-diphenylprop acyloxy)-7, 9, 9-trimethyl-3-oxa--9-nitrogen three ring [3.3.1.0*2, 4*] nonane salt, 7-hydroxyl-7, 9, 9-trimethyl-3-oxa--9-nitrogen three ring [3.3.1.0*2, 4*] the nonane 9-methyl-9H-root and stem of certain plants-9-formic acid esters salt, it is all optionally in its racemic modification, its enantiomer, its diastereomer with and composition thereof form, and optionally in the form of its pharmacology compatibility acid-addition salts.In described salt, chloride, bromide, iodide and mesylate are preferred.

Select in the group that other therapeutic agent especially preferred is made up of following compound: mometasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, tiotropium salt, glycopyrronium salt, 3-[2-hydroxyl-2, two (2-thienyl) acetoxyl group of 2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt (especially Ah 's ammonium salt, be preferably aclidinium bromide), 1-(2-phenethyl)-3-(9H-ton-9-base carbonyl oxygen base)-1-nitrogen dicyclo [2.2.2] octane salt, rolipram, roflumilast, cilomilast and No. WO03/097613rd, PCT patent application case, No. WO2004/058729, No. WO2005/049581, compound required for protection in No. WO2005/123693 and No. WO2005/123692.

Therefore, one aspect of the present invention provides compound of the present invention as herein defined and corticosteroid, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

The present invention also provides compound of the present invention, and it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein, and wherein compound of the present invention and corticosteroid are used jointly.

The present invention also provides corticosteroid, and it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein by jointly using with compound of the present invention.

The corticosteroid that especially preferred corticosteroid is selected for the group be made up of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.

Another aspect of the present invention provides compound of the present invention as herein defined and cholilytic drug and optional corticosteroid, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

The present invention also provides compound of the present invention as herein defined; it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein, and wherein compound of the present invention and cholilytic drug and optional corticosteroid are used jointly.

The present invention also provides cholilytic drug, and it is for by jointly using with compound of the present invention and optional corticosteroid and make pulmonary function (especially FEV1) normalization of human patients as defined herein.

Especially preferred cholilytic drug is the cholilytic drug that the group be made up of tiotropium salt, glycopyrronium salt, 3-[two (2-thienyl) acetoxyl group of 2-hydroxyl-2,2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt and 1-(2-phenethyl)-3-(9H-ton-9-base carbonyl oxygen base)-1-nitrogen dicyclo [2.2.2] octane salt is selected.Select in the group that optional corticosteroid is preferably made up of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.

Another aspect of the present invention provides compound of the present invention as herein defined and PDE4 inhibitor and optional corticosteroid and/or cholilytic drug, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

The present invention also provides compound of the present invention as herein defined; it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein, and wherein compound of the present invention and PDE4 inhibitor and optional corticosteroid and cholilytic drug are used jointly.

The present invention also provides PDE4 inhibitor, and it is for by jointly using with compound of the present invention and optional corticosteroid and/or cholilytic drug and make pulmonary function (especially FEV1) normalization of human patients as defined herein.

The PDE4 inhibitor of especially preferred PDE4 inhibitor for selecting in the group that is made up of compound required for protection in rolipram, roflumilast, cilomilast and PCT patent application case No. WO03/097613, No. WO2004/058729, No. WO2005/049581, No. WO2005/123693 and No. WO2005/123692.Select in the group that optional corticosteroid is preferably made up of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.Select in the group that optional cholilytic drug is preferably made up of tiotropium salt, glycopyrronium salt, 3-[two (2-thienyl) acetoxyl group of 2-hydroxyl-2,2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt and 1-(2-phenethyl)-3-(9H-ton-9-base carbonyl oxygen base)-1-nitrogen dicyclo [2.2.2] octane salt.

Especially preferred embodiment of the present invention provides 3-[the 2-hydroxyl-2 of compound of the present invention as herein defined and treatment effective dose; two (2-thienyl) acetoxyl group of 2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt and optional corticosteroid and/or PDE4 inhibitor, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

Compound of the present invention as herein defined is also provided; it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein; wherein 3-[2-hydroxyl-2,2-two (2-thienyl) acetoxyl groups]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] the octane salt of compound of the present invention and treatment effective dose and optional corticosteroid and/or PDE4 inhibitor are used jointly.

3-[the 2-hydroxyl-2 for the treatment of effective dose is also provided; two (2-thienyl) acetoxyl group of 2-]-1-(3-phenoxy propyl)-1-nitrogen dicyclo [2.2.2] octane salt, it is for by jointly using with compound of the present invention and optional corticosteroid and/or PDE4 inhibitor and make pulmonary function (especially FEV1) normalization of human patients as defined herein.

Another especially preferred embodiment of the present invention provides compound of the present invention as herein defined and the treatment mometasone furoate of effective dose and optional cholilytic drug and/or PDE4 inhibitor, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

Compound of the present invention as herein defined is also provided; it is for making pulmonary function (especially FEV1) normalization of human patients as defined herein, and wherein compound of the present invention and the treatment mometasone furoate of effective dose and optional cholilytic drug and/or PDE4 inhibitor are used jointly.

Also provide the mometasone furoate for the treatment of effective dose, it is for by jointly using with compound of the present invention and optional cholilytic drug and/or PDE4 inhibitor and make pulmonary function (especially FEV1) normalization of human patients as defined herein.

An alternative embodiment of the invention provides compound of the present invention as herein defined, corticosteroid, cholilytic drug and PDE4 inhibitor, its simultaneously, simultaneously respectively or sequentially for making pulmonary function (especially FEV1) normalization of human patients as defined herein.

Usually, the disease of described patients's respiratory tract disease (such as asthma or COPD) and/or reduction pulmonary function.

Usually, the medical composition comprising compound of the present invention and pharmaceutically acceptable supporting agent is suitable for using by sucking and also can comprising one or more other therapeutic agents as herein defined for the treatment of effective dose.But, the local of other form any, parenteral or oral administration may be there is.The dosage form using suction embodies preferred administration form, especially like this in the therapy of pulmonary disease or disease.

Medical composition can be prepared according to the either method known in pharmaceutics technology.All methods include the step that active ingredient is combined with supporting agent.Generally speaking, by making active ingredient and liquid carrier or Fine-powdered solids supporting agent or both evenly and being closely combined and then (if desired) makes product be shaped to desired form to prepare medical composition.

Supporting agent for the medical composition of dry powder form is selected from starch or pharmaceutically acceptable sugar (such as lactose or glucose) usually.Lactose is preferred.

Other supporting agent be applicable to is found in Remington:TheScienceandPracticeofPharmacy, the 20th edition, and LippincottWilliams & Wilkins, Philadelphia, Pa., in 200.

Medical composition for sucking is sent by means of inhaler (such as Diskus, aerosol or aerosol apparatus).Described inhaler is constructed to one or more other therapeutic agents as herein defined of delivery treatments effective dose after actuation usually.

Compound of the present invention is packaged in inhaler and can be suitable for unit dose or multiple dose is sent.When multiple dose is sent, compound of the present invention can measure in advance or measure in use.

Inhaler is generally monodose inhaler, multiple-units dosage inhaler or multiple dose device inhaler.

For can (such as) be provided in the capsule of (such as) gelatin and the bubble-cap (blister) of cartridge case (cartridge) or (such as) laminated aluminium foil, in inhaler or insufflator by sucking local delivery to the dry powder composite of lung.

Diskus is divided into three groups: (a) single dose, (b) multiple-units dosage and (c) multiple dose device.

For the inhaler of the first kind (a), single dose is own to be weighed in small container by manufacturer, and it is hard gelatin capsule mainly.Capsule must be obtained by individual boxes or container and insert in the reception area of inhaler.Then, capsule must be opened with pin or cutting knife (cuttingblade) or bore a hole to allow a part during sucking to suck air stream through capsule to take away powder or to discharge powder by these perforates by capsule by means of centrifugal force.After suction, capsulae vacuus must remove from inhaler again.Inserting and removing capsule needs to take inhaler apart usually, and this operation may be difficult and troublesome for some patients.

Other shortcoming relevant with using hard gelatin capsule inhalation of dust is that (a) prevents that the ability being absorbed moisture by surrounding air is weak, (b) and open or bore a hole after capsule is exposed to extreme relative humidity (this can cause rupture or indenture (indenture)) in advance relevant problem and (c) may suck capsule fragment.In addition, for multiple capsule inhaler, oneself not exclusively discharges by report people such as (, 1997) such as Nielsen.

As described in WO92/03175, some capsule inhaler have storehouse casket (magazine), by described storehouse casket, each capsule can be transferred to receiving chamber, carry out boring a hole and emptying in described receiving chamber.Other capsule inhaler has such rotating cabin casket, and it is with can be corresponding with air conduit with the capsule chamber of discharge dosage (such as WO91/02558 and GB2242134).It comprises the type of multiple-units dosage inhaler (b) and bubble-cap type inhaler, and it supplies limited amount unit dose on pan or ribbon.

Compared with capsule inhaler, bubble-cap type inhaler provides the good moisture protection of medicament.By at covering and the enterprising eleven punch 11 of blister foil or obtain powder by strip off cover foil.When using bubble-cap type ribbon to substitute pan, dosage number can be increased, but patient changes empty strip is inconvenient.Therefore, the described device be incorporated to sosimetric system is normally deserted, and it comprises for belt thing and opens the technology of blister pouch.

Multiple dose device (c) containing premeasuring containing medicament powder.It is made up of relatively large container and the dosage measurement assembly (dosemeasuringprinciple) that must be operated by patient.Described container is with the multiple dosage be separated with body of powder individually by volume dispatch (volumetricdisplacement).There is multiple dosage measurement assembly, comprise rotatable film (such as EP0069715) or pan (such as GB2041763; EP0424790; DE4239402 and EP0674533), Rotatable circular cylindrical shell (such as EP0166294; GB2165159 and WO92/09322) and rotatable frustum (such as WO92/00771), all there is the cavity of the powder must filled from container.Other multiple dose device has measurement piston, its have local or circumferential groove with by the powder of certain volume by container dispatch to (such as EP0505321, WO92/04068 and WO92/04928) in delivery chamber or air conduit; Or measurement slide block, such as NovolizerSD2FL (such as Sofotec), also referred to as it has description in following patent application case: No. WO97/000703, No. WO03/000325 and No. WO03/061742.

Can reproduce dosage measurement is one of main concern item of multiple dose suction apparatus.Powder composite must show good and stable flowing property, because the filling of dosage measurement cup or cavity is mainly by the impact of gravity.For loading type monodose inhaler and multiple-units dosage inhaler again, dosage measurement degree of accuracy and repeatability can be guaranteed by manufacturer.On the other hand, multi-dose inhaler can contain obviously the dosage of more high reps, and generally can reduce the number of processes of filling dosage.

Because the suction air circulation in multiple dose device often cuts across dosage measurement cavity, and because multi-dose inhaler large and the dosimetry system of rigidity can not be stirred by this suction air stream, take away powder mass by cavity so easy and during ejection produce few deagglomeration (de-agglomeration).

Therefore, independent disintegrate component is required.But, in fact, its not always inhaler design a part.Due to the dosage of high reps in multiple dose device, therefore it is minimized and/or must these parts of cleaned at regular intervals possibly to make to stick to powder on the inwall of air conduit and pine group component, and does not affect the doses remaining in device.Some multi-dose inhalers have deserted medicament reservoir, and it can carry out changing (such as WO97/000703) after oneself takes stipulated number dosage.For the described semipermanent multi-dose inhaler with deserted medicament reservoir, even stricter to preventing the requirement of drug accumulation.

Advantageously, for there is controlled particle diameter by sucking the medicament used.Be generally 1-10 micron for the most preferably particle diameter sucked in bronchi, be preferably 2-5 micron.When suck arrive tracheole time, it is generally excessive that size is greater than the particle of 20 microns.For obtaining these particle diameters, reduce the particle size of produced active ingredient by conventional method (such as passing through micronization).Required part is by air classification or sieve and isolate.Described particle is preferably crystal form.

Be difficult to realize its high dose repeatability due to the bad mobility of micronised powder and extremely cohesion tendency.For improving the efficiency of dry powder composite, should be comparatively large when particle is in inhaler, but should be less when being expelled in respiratory tract.Therefore, the such as excipient such as lactose or glucose is generally used.In the present invention, the particle diameter of excipient is usually by more much bigger than the medicament sucked.When excipient is lactose, it provides with lactose (the being preferably crystalline alpha lactose monohydrate) form through grinding usually.

Except being used by Diskus, compositions of the present invention is using spray device, metered-dose inhaler and aerosol-applied also, it operates via gaseous propellant or by means of so-called nebulizer, under high pressure can spray the solution of pharmacological active substance thus thus produce can the mist of Inhaled Particles After Acute.Described aerosol apparatus (such as) is described in WO91/14468 and WO97/12687.

These liquid formulation are generally containing suitable supporting agent, and it can be the propellant used for MDI or the water for using via aerosol apparatus.Composite can comprise other component, such as antiseptic (such as benzalkonium chloride, potassium sorbate, benzyl alcohol); PH value stabilizing agent (such as acidizer, alkaline agent, system buffer); Isotonic stabilizing agent (such as sodium chloride); Surfactant and wetting agent (such as polysorbate, sorbitan ester); And/or absorption enhancer (such as chitosan, hyaluronic acid, surfactant).Composite also can containing additive to improve the dissolubility of other reactive compound when mixing with salt of the present invention.Solubility enhancer can comprise the component of such as cyclodextrin, liposome or cosolvent (such as ethanol, glycerol and propylene glycol) and so on.

Other supporting agent being applicable to the composite of active salt of the present invention is found in Remington:TheScienceandPracticeofPharmacy, the 20th edition, and LippincottWilliams & Wilkins, Philadelphia, Pa., in 2000.

Pressurised aerosol compositions is generally filled in the tank being equipped with valve (being especially metering valve).Tank optionally scribbles plastic material, such as, fluorocarbon polymer described in WO96/32150.Tank is coordinated with the actuator being suitable for intraoral delivery.

The present invention also provides a kind of method making pulmonary function (especially FEV1) normalization of human patients; described method comprises the compound to described patient therapeuticallv's effective dose; described compound is the 5-(2-{ [6-(2 of racemic modification, stereoisomer or stereoisomer mixture form; 2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one (i.e. the hydroxyquinoline ketone derivatives of formula (I)) or its pharmaceutically acceptable salt or solvate

The present invention also provides the purposes of compound in the medicament manufacturing pulmonary function (especially FEV1) normalization for making human patients; described compound is the 5-(2-{ [6-(2 of racemic modification, stereoisomer or stereoisomer mixture form; 2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one (i.e. the hydroxyquinoline ketone derivatives of formula (I)) or its pharmaceutically acceptable salt or solvate

Example 1

The clinical II phase is studied: the activity of 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one half napadisilate of the single dose that asthmatic patient sucks, safety, toleration and pharmacokinetics are evaluated in the cross matching utilizing randomization double blinding, dual analog, placebo and expression activitiy group to control.

Method: by suffer from diagnosis before screening as 2006GINA criterion define slight to moderate persistent asthma at least 6 months and people's randomization of 61%-85% that FEV1 be expectation normal value (according to the people such as Quanjer 1993) carry out processing order, it comprises: use single dose 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one half napadisilate ( with the metering nominal standard dose of 25 micrograms in device); Use twice (time point is 0 hour and 12 hours) salmaterol ( with the metering nominal standard dose of 50 micrograms in device) and use placebo by means of Diskus to everyone.Pulmonary function measures and comprises (by vital capacity measurement method) FEV1, PEF, FVC, FEF25-75 and (by body volume cardiotokography) sGaw and Raw.

Result: 25 male (18 to 70 years old) participate in research.Compared with placebo and salmaterol, 5-(2-{ [6-(the fluoro-2-phenyl ethoxy of 2,2-bis-) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one (25 microgram) significantly increase average peak and valley FEV1.Surprisingly, even if compared with the salmaterol used with two doses, the increase of average valley FEV1 also has statistical significance.The descriptive data that do not correct obtained is shown in following table.

Peak F EV1

Valley FEV1

As shown in fig. 1, within the period of whole 24 hours, observe the remarkable normalization of pulmonary function as shown in above-mentioned FEV1 value, and produce clinical relevant effect.Similar trend can be seen with PEF, FVC, FEF25-75, sGaw and Raw.

Conclusion: the 5-(2-{ [6-(2 of single dose; 2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-(R)-ethoxy)-oxine-2 (1H)-one (25 microgram) causes bronchiectatic activity large and lasting unexpectedly and quick acting, and this makes the remarkable normalization of pulmonary function.This is proven by obtained high FEV1 value, and described FEV1 value is significantly higher than the value produced by salmaterol.

Claims (1)

1. compound for the preparation of by suck and as the purposes in the medicament with the maintenance therapy of the chronic respiratory patient of intractable symptom nonreactive to other bronchodilators, wherein this compound is 5-(2-{ [6-(2,2-bis-fluoro-2-phenyl ethoxy) hexyl] amido }-1-ethoxy)-oxine-2 (1H)-one or its pharmaceutically acceptable salt or the solvate of racemic modification, stereoisomer or stereoisomer mixture form.